The role of human dopamine transporter in NeuroAIDS.
The role of human dopamine transporter in NeuroAIDS.
复制标题
DOI：
10.1016/j.pharmthera.2017.10.007
复制
发表时间：
2018-03
影响因子：
13.5
通讯作者：
Zhan CG
中科院分区：
文献类型：
--
作者：
Zhu J;Ananthan S;Zhan CG
HIV相关神经认知障碍(Hand)在HIV感染者中仍然非常普遍，是一组特殊的神经病理疾病，与HIV-1病毒蛋白相关，如转录反式激活因子(Tat)蛋白。可卡因滥用会增加手部疾病的发病率，并通过促进病毒复制而加剧其严重程度。多巴胺能传递的紊乱已被认为是手部疾病的危险因素之一。突触前多巴胺转运体(DAT)对DA动态平衡和多巴胺能调节包括认知在内的脑功能是必不可少的。TAT和可卡因通过直接作用于人的DAT(HDAT)协同作用于突触DA水平，最终导致DA传递的失调。通过集成的计算模型和实验验证，HDAT中的关键残基已经被确定，它们在TAT诱导的DAT抑制和诱导转运体构象转变中发挥关键作用。本文综述了与HIV感染相关的DAT介导的多巴胺能系统的神经学变化、DAT介导的对TAT的适应性反应以及新化合物对HDAT的变构调节作用的最新信息。了解TAT诱导DAT介导的DA系统失调的分子机制，对于寻找新的靶点进行早期的手治疗干预具有重要的临床意义。
HIV-associated neurocognitive disorder (HAND) remains highly prevalent in HIV infected individuals and represents a special group of neuropathological disorders, which are associated with HIV-1 viral proteins, such as transactivator of transcription (Tat) protein. Cocaine abuse increases the incidence of HAND and exacerbates its severity by enhancing viral replication. Perturbation of dopaminergic transmission has been implicated as a risk factor of HAND. The presynaptic dopamine (DA) transporter (DAT) is essential for DA homeostasis and dopaminergic modulation of the brain function including cognition. Tat and cocaine synergistically elevate synaptic DA levels by acting directly on human DAT (hDAT), ultimately leading to dysregulation of DA transmission. Through integrated computational modeling and experimental validation, key residues have been identified in hDAT that play a critical role in Tat-induced inhibition of DAT and induce transporter conformational transitions. This review presents current information regarding neurological changes in DAT-mediated dopaminergic system associated with HIV infection, DAT-mediated adaptive responses to Tat as well as allosteric modulatory effects of novel compounds on hDAT. Understanding the molecular mechanisms by which Tat induces DAT-mediated dysregulation of DA system is of great clinical interest for identifying new targets for an early therapeutic intervention for HAND.
登录
查看更多内容
影响因子：
5.7
作者：
Chang, Linda;Wang, Gene-Jack;Fowler, Joanna S.
通讯作者：
Fowler, Joanna S.
影响因子：
5.3
作者：
Bertrand, Sarah J.;Aksenova, Marina V.;Mactutus, Charles F.;Booze, Rosemarie M.
通讯作者：
Booze, Rosemarie M.
影响因子：
4
作者：
Castelo-Branco, G;Rawal, N;Arenas, E
通讯作者：
Arenas, E
影响因子：
3.7
作者：
Chao, Herta H.;Hu, Sien;Li, Chiang-shan R.
通讯作者：
Li, Chiang-shan R.
影响因子：
15.1
作者：
Acharjee, Shaona;Branton, William G.;Power, Christopher
通讯作者：
Power, Christopher